The binding of IgE to high-affinity IgE receptors (FcepsilonRI) expressed on the surface of mast cells and basophils primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of pro-inflammatory mediators which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen- specific effector cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and can also contribute to host defense. Approximately 20 years ago, two groups independently reported that the level of FcepsilonRI expression on circulating human basophils can exhibit a strong positive correlation with the serum concentration of IgE. However, the basis for this association was not determined. We have recently found that exposure to IgE results in a striking (up to 32-fold) up-regulation of surface expression of FcepsilonRI on mouse or human mast cells in vitro or on mouse peritoneal mast cells or bone marrow basophils in vivo. Moreover, baseline levels of FcepsilonRI expression on peritoneal mast cells or bone marrow basophils from genetically IgE-deficient (IgE -/-) mice are dramatically reduced (by 80%) compared to those On cells from the corresponding normal mice. IgE-dependent upregulation of FcepsilonRI expression in turn significantly enhances the ability of mast cells to release mediators and cytokines upon challenge with IgE and specific antigen. We therefore wish to use in vitro, in vivo, biochemical and genetic approaches to test two related hypotheses: 1) The binding of monomeric IgE to FcepsilonRI can significantly enhance surface expression of FcepsilonRI on mast cells and basophils (and perhaps eosinophils and macrophages) via a mechanism which can be modulated by cytokines and other factors, but which results in little or no activation of mediator secretion; and 2) Such IgE-dependent up-regulation of FcepsilonRI expression not only increases the capacity of these effector cells to be adequately sensitized with larger numbers of different IgE species of distinct antigenic specificities, but enhances effector cell function, e.g., by permitting mast cells to release mediators in response to antigen challenge with increased sensitivity and intensity, and that these effects, in turn, can result in amplification of the expression of IgE-dependent immune responses in vivo.